A pharmacokinetic (PK) study of AC480 administered twice daily in patients with surgically resectable, recurrent malignant glioma (MG) not on enzyme-inducing antiepileptic drug (EIAED).
2070 Background: AC480 is a novel oral tyrosine kinase inhibitor of the human epidermal growth factor receptor family, especially EGFR and HER2. EGFR is an important therapeutic target in MG. We performed a pilot study to evaluate the tumor and plasma PK of AC480 among patients with recurrent MG. METHODS: Eligibility included: adult patients with < three recurrences of a WHO grade 3 or 4 MG; candidate to surgical resection; prior treatment with radiotherapy and chemotherapy; Karnofsky >60%; adequate hematologic, renal and liver function. Exclusion included use of EIAED and prior targeted therapies to EGFR and HER2. FDG-PET was obtained at baseline, then AC480 was initiated at 300 mg orally BID. FDG-PET was repeated on day 14. Patients remained on treatment until surgery (day16). Plasma PK were obtained on days 1, 14 and 16. Tumor specimen for tumor PK was obtained at surgery. Patients resumed AC480 7 to 21 days post-surgery. RESULTS: As planned, 5 patients were enrolled on study (WHO grade 4, n=4; WHO grade 3, n=1). Median age was 58 (range, 36-65). All patients completed FDG-PET and surgery. Three patients had same or decreased metabolic activity on day 14 FDG-PET; two had increased metabolic activity. Following surgery, 4 patients resumed therapy, one patient refused, as pathology showed WHO grade 2. One patient remains on therapy after 45+ weeks. Two patients progressed 4 weeks after resuming AC480 and one after 8 weeks. One patient each experienced grade 3 proteinuria and leukopenia. Tumor PK levels were variable, but AC480 was present in all samples. Concentrations ranged from 2561 to 8703 ng/mL (5 to 16 uM). Tumor/Plasma PK ratios ranged from 3 to 11, indicating tumor levels exceeded plasma levels in all patients. CONCLUSIONS: AC480 is well tolerated and reaches the brain with tumor PK levels exceeding plasma. Further trials combining AC480 with chemotherapy or other targeted therapies are warranted.
Desjardins, A; Reardon, DA; Vredenburgh, JJ; Peters, K; Trikha, M; James, J; Gardner, M; Brickhouse, A; Herndon, JE; Friedman, HS
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